G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors, and are the targets of a substantial fraction of all prescribed ad abused drugs. It is widely accepted that members of the largest GPCR family (class A receptors) self-assemble as dimers or higher-order oligomers, and GPCR dimers have been proposed as potential targets for novel therapeutic drugs. However, functional consequences of dimerization have been described for only a few receptors, and ligands that bind specifically to dimers have not been found. The main goal of this project is to test the hypothesis that most interactions between classes A protomers are both transient and structurally nonspecific. If this is the case, it would explain why dimerization is rarely leads to overt functional changes or unique binding sites. The objective of the proposed project is to determine the physical stability of interactions between a large sample of class A receptors and transmembrane control proteins using fluorescence resonance energy transfer (FRET), bioluminescence resonance energy transfer (BRET), time-resolved fluorescence resonance energy transfer (TR-FRET), and an affinity-based on-cell corecruitment assay. Inclusion of a large sample of non-GPCR control proteins will allow us to determine if physical interactions between classes A protomers are special, or are typical of interactions between polytopic transmembrane proteins in general. These experiments will better define the quaternary structure of the largest subfamily of GPCRs, and may force a revision of the standard model that currently motivates the search for dimer-selective drugs.